Scientists from Valencia University (UV) have discovered that Rilpivirine, an antiretroviral drug used for treating HIV, has beneficial effects on chronic liver diseases. The finding opens a path to identify new therapies for liver diseases. Their work has been published in the journal Gut.
Liver fibrosis is a significant health issue worldwide due to its growing prevalence and the lack of effective therapeutic options.
Recently, researchers from the UV and the CIBERehd (Biomedical Research Centre Network—Hepatic and Digestive Diseases) have revealed that antiretroviral medicine Rilpivirine (RPV), which is already sold and used for treating HIV infections, can decrease liver fibrosis in different preclinical models of hepatic damage.
The results obtained and published in Gut highlight the need to find selective therapies to efficiently treat patients with fibrosis, acting on the inactivation of stellate cells and the regeneration of liver tissue.
The study reveals that RPV prevents the accumulation of lipids and has anti-inflammatory and anti-fibrotic effects on preclinical models of chronic liver disease, regardless of their aetiology, which is of great clinical significance because hepatic fibrosis is a common factor in all chronic liver diseases.
The protective effect of this drug has been confirmed in a retrospective study analyzing the clinical data from published databases on patients infected by HIV and treated with different antiretroviral regimens, which shows that patients treated with this medicine show an improved liver function.
OBJECTIVE:
Liver fibrosis constitutes a major health problem worldwide due to its rapidly increasing prevalence and the lack of specific and effective treatments.
Growing evidence suggests that signalling through cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways regulates liver fibrosis and regeneration.
Rilpivirine (RPV) is a widely used anti-HIV drug not reported to produce hepatotoxicity. We aimed to describe the potential hepatoprotective effects of RPV in different models of chronic liver injury, focusing on JAK-STAT signalling regulation.
DESIGN:
The effects of RPV on hepatic steatosis, inflammation and fibrogenesis were studied in a nutritional mouse model of non-alcoholic fatty liver disease, carbon tetrachloride-induced fibrosis and bile duct ligation-induced fibrosis.
Primary human hepatic stellate cells (hHSC) and human cell lines LX-2 and Hep3B were used to investigate the underlying molecular mechanisms.
RESULTS:
RPV exerted a clear anti-inflammatory and antifibrotic effect in all the in vivo models of liver injury employed, and enhanced STAT3-dependent proliferation in hepatocytes and apoptosis in HSC through selective STAT1 activation.
These results were reproduced in vitro; RPV undermined STAT3 activation and triggered STAT1-mediated pathways and apoptosis in HSC.
Interestingly, this selective pro-apoptotic effect completely disappeared when STAT1 was silenced. Conditioned medium experiments showed that HSC apoptosis activated STAT3 in hepatocytes in an interleukin-6-dependent mechanism.
CONCLUSION:
RPV ameliorates liver fibrosis through selective STAT1-dependent induction of apoptosis in HSC, which exert paracrinal effects in hepatocytes, thus promoting liver regeneration. RPV’s actions may represent an effective strategy to treat chronic liver diseases of different aetiologies and help identify novel therapeutic targets.
More information: Alberto Martí-Rodrigo et al. Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells, Gut (2019). DOI: 10.1136/gutjnl-2019-318372
Journal information: Gut
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